Among the three classes of opioid receptor subtypes, designated delta (δ), kappa (κ), and mu (μ), a substantial body of evidence suggests that subtype-selective opioid receptor agents and mixed agonists-antagonists exhibit pharmacologically relevant effects. Of particular relevance in the present instance, δ-selective opioids are potentially useful as analgesics devoid of the numerous side effects (e.g., respiratory depression, physical dependence and gastrointestinal effects) associated with narcotics such as morphine (E. J. Bilsky et al., J. Pharmacol. Exp. Ther., 273, 359 (1995)). Moreover, selective antagonists of δ receptors have been shown to modulate the development of tolerance and dependence to μ agonists such as morphine (E. E. Abdelhamid et al., J. Pharmacol. Exp. Ther., 258, 299 (1991)), to modulate the behavioral effects of drugs of abuse such as cocaine (L. D. Reid et al., Life Sci., 52, PL67 (1993)), and to elicit favorable immunomodulatory effects (R. V. House et al., Neurosci. Lett., 198, 119 (1995)). The δ-selective opioids thus represent extremely attractive candidates for a broad range of novel pharmaceutical applications including powerful yet safe analgesics, immunomodulatory agents for treating immune disorders, and new treatments for drug addiction. Likewise, agents acting alone or in combination with mixed agonist-antagonist activity among the opioid receptor subtypes remain the subject of intense interest and research in the pharmaceutical industry.
Opioid narcotics can be potent painkillers, but they are also addictive. The delta (δ) receptors, along with the related kappa (κ) and mu (μ) receptors, are found on cells located throughout the central and peripheral nervous system. The receptors normally bind with opioid peptides (e.g., enkephalins) that the body produces. By binding to the receptors, these peptides modulate endocrine, cardiovascular respiratory, gastrointestinal, and immune functions. Opioid narcotics are alkaloids, with molecular structures quite distinct from opioid peptides. However, the narcotic drugs and opioid peptides share common structural features (known as pharmacophores) that enable the drugs to bind to the opioid receptors. When they bind to these receptors, the narcotics exert various effects on the perception of pain, consciousness, motor control, mood, and autonomic function. They also induce physical dependence. However, recently published studies demonstrate that compounds, or combinations of compounds, that act in concert as selective μ agonists and δ antagonists (mixed μ/δ agonists) exhibit the potency of opioid pain killers without their negative side effects, such as physical addiction, physical dependence, narcotic addiction, and like conditions. See P. W. Schiller et al., J. Med. Chem., 42, 3520 (1999).
As one example of the value of subtype-selective opioid receptor agents, recent evidence suggests that δ-selective opioids are potentially useful as analgesics devoid of the numerous side effects (e.g., respiratory depression, physical dependence and gastrointestinal effects) associated with narcotics such as morphine (E. J. Bilsky et al., J. Pharmacol. Exp. Ther., 273, 359 (1995)). Moreover, selective antagonists of δ receptors have been shown to modulate the development of tolerance and dependence to μ agonists such as morphine (E. E. Abdelhamid et al., J. Pharmacol. Exp. Ther., 258, 299 (1991)), to modulate the behavioral effects of drugs of abuse such as cocaine (L. D. Reid et al., Life Sci., 52, PL67 (1993)), and to elicit favorable immunomodulatory effects (R. V. House et al., Neurosci. Lett., 198, 119 (1995)). The δ-selective opioids thus represent extremely attractive candidates for a broad range of novel pharmaceutical applications including powerful yet safe analgesics, immunomodulatory agents for treating immune disorders, and new treatments for drug addiction.
Therefore, a need exists for non-opioid compounds which possess high binding affinity and high selectivity for delta (δ), kappa (κ), and mu (μ) opioid receptors. Such compounds would be useful for treating pain as well as other opioid-related conditions.